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NEFH – Amyotrophic Lateral Sclerosis

Heterozygous missense variants in NEFH have been identified in multiple sporadic ALS cohorts, supporting an autosomal dominant contribution to disease risk. In a Chinese cohort of 371 sALS patients, one novel NEFH variant, c.2602G>A (p.Glu868Lys), was detected (PMID:31788332). In a Hungarian series of 107 ALS patients, rare NEFH variants were found in 3.7% of cases, including c.443G>C (p.Arg148Pro), c.1514C>T (p.Pro505Leu) and c.1013C>T (p.Thr338Ile) (PMID:31475037). A two-phase case-control study in Chinese subjects identified rs568759161 (c.2360G>C (p.Ser787Arg)) at a higher frequency in 9/1342 cases versus 2/3574 controls (OR 12.06; P = 0.0003) (PMID:34511133). No familial segregation of ALS was reported for these variants.

Functional evidence for ALS-associated NEFH variants is currently lacking. However, frameshift mutations causing cryptic amyloidogenic element translation have been characterized in CMT2CC, demonstrating protein aggregation, autophagic recognition and caspase-3-mediated apoptosis in neuronal models and in vivo (PMID:28709447). These studies imply a toxic gain-of-function mechanism potentially relevant to motor neuron degeneration.

Key Take-home: While rare NEFH missense variants and a risk allele p.Ser787Arg have been associated with sporadic ALS, the evidence remains limited; NEFH is not yet a validated diagnostic gene for ALS.

References

  • Aging and disease • 2019 • Genetic Spectrum and Variability in Chinese Patients with Amyotrophic Lateral Sclerosis. PMID:31788332
  • Frontiers in genetics • 2019 • Comprehensive Genetic Analysis of a Hungarian Amyotrophic Lateral Sclerosis Cohort. PMID:31475037
  • BMC medical genomics • 2021 • Sequencing of neurofilament genes identified NEFH Ser787Arg as a novel risk variant of sporadic amyotrophic lateral sclerosis in Chinese subjects. PMID:34511133
  • Acta neuropathologica communications • 2017 • Cryptic amyloidogenic elements in mutant NEFH causing Charcot-Marie-Tooth 2 trigger aggresome formation and neuronal death. PMID:28709447

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

Rare heterozygous NEFH variants identified in sporadic ALS cohorts ([PMID:31788332], [PMID:31475037]) and a case-control risk allele p.Ser787Arg with modest OR ([PMID:34511133]), lacking segregation

Genetic Evidence

Limited

NEFH variants found in <5% of sALS cases across cohorts; one risk allele with nominal significance ([PMID:34511133])

Functional Evidence

Limited

CMT2-associated NEFH frameshifts produce neurotoxic aggregates in neuronal and in vivo models ([PMID:28709447]), but ALS-specific functional data are absent